Cancers are one of major diseases which threaten human's health, and are diseases caused by a process where cells are subjected to a series of mutations, and proliferated and immortalized in an unlimited and uncontrolled manner. Causes of cancer occurrence are environmental or external sources such as chemical substances, viruses, bacteria, ionizing radiation, and the like, or internal sources such as inherited genetic change, and the like (Klaunig & Kamendulis, Annu Rev Pharmacol Toxicol., 44:239-267, 2004). When cancers are discovered in their initial stage, therapy, such as surgery, radiation therapy, chemotherapy, and the like, can be performed, but there are big concerns that side effects are accompanied therewith. In the case of terminal cancers or metastatic cancers, there are no special therapies and patients are given limited time period to live.
Recently, various biochemical mechanisms associated with cancers have been identified, and therapeutic agents thereagainst have been developed. However, no basic treatment methods for cancers have been suggested until now. Thus, studies aiming to identify various in vivo molecules related to cancers and develop drugs targeting at these molecules have been actively progressed. Also, an effort to enhance the effect of treating cancers has been made by combining part of these drugs. Therefore, an effort to additionally discover target molecules related to cancers is very important.
The phosphatase and tensin homolog (PTEN) tumor suppressor, a major negative regulator in phosphatidylinositol-3-kinase (PI3K) signal transfer step, is known as the most frequently mutated and deleted genes in human cancers. According to recent studies, important questions related to ubiquitination in regulating the functions of the tumor suppressor PTEN are raised, and the studies for regulating mechanisms required for PTEN ubiquitination have been continuously conducting.
The present inventors found during the studies on PTEN mechanism related to ubiquitination that p34 protein, a binding partner of neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1), controls the stability of NEDD4-1 protein, and thereby controls the conversion of PTEN mono- and poly-ubiquitination.
Specifically, an increase in p34 expression interacts with the WW1 domain of NEDD4-1, an E3 ubiquitin ligase, and enhances its protein stability, which result in PTEN poly-ubiquitination and PTEN protein degradation, whereas p34 knockdown causes PTEN mono-ubiquitination and promotes nuclear localization of PTEN, which result in inhibiting Akt pathways related to survival, proliferation, invasive properties, and metastatic properties of tumors.
Thus, the present inventors confirmed that p34 may act as a key regulator in PTEN ubiquitination pathway by regulating NEDD4-1 protein stability, and particularly may be an effective target for treatment of a cancer associated with NEDD4-1 and PTEN, and then completed the present invention.